- Seronegative spondyloarthropathies are a group of inflammatory disease in which the spine, peripheral joints, skin, eyes, and other tissues of the body may be involved. There is a strong association of the HLA-B27 antigen in several of the diseases. In most cases, the disease occurs after gastrointestinal infection with one of several species of enterobacteria. The applicants have been successful in generating spontaneous inflammatory arthritis and nail changes in their HLA-B27 transgenic mice lacking endogenous mouse beta-2 microglobulin. The disease is primarily found in the male mice. Their studies suggest that the disease is mediated by free HLA-B27 heavy chains on the cell surface. In this proposal, they will completely characterize the spontaneous disease in these mice by a through immunogenetic dissection. First of all, they will confirm the specificity of the B27 molecule in the disease process by studying other class I transgenic mice. Next, they will determine the potential role of class I versus class II molecules in this disease process by using a class II knock-out (Abo) gene. Next, they will determine the role of CD4 T cells versus CD8 T cells in the disease process by introducing CD4 knock-out and CD8 knock-out genes into their B27 transgenic mice. The final genetic study would be done to determine whether transporter genes (Tap), proteasome (Lmp), and T cell receptor rearrangement (Rag) genes play a role in this disease. They will determine the role of class I, class II, CD4, and CD8 T cells in the initiation phase versus the effector phase by antibody initiation studies prior to the initiation of the disease and after the onset of the disease. In the second set of experiments, they will try to identify the endogenous/environmental antigen which causes the triggering of the disease by eluting the peptides from the B27 molecules and comparing them with those from the mice in the pathogen-free colony. They will try to induce the disease in the pathogen-free B27 mice by injecting them with enterobacterial peptides with B27 binding motifs. In the final aim of this proposal, they will determine whether collagen is a target in the pathogenesis of the disease. These studies, they expect, will open up new insights into the immunogenetics of human spondyloarthropathy.